ArticlesComparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis
Introduction
Schizophrenia is a debilitating disease, ranked among the top 20 causes of disability worldwide.1 The question of which antipsychotic drug should be preferred for treatment of the disease is controversial, largely because of the substantial costs of second-generation antipsychotic drugs (estimated US$14·5 billion globally in 2014).2 New antipsychotic drugs such as asenapine, iloperidone, lurasidone, and paliperidone continue to be marketed, but as earlier second-generation drugs come off patent, an important question is whether the newest drugs are cost effective. Previous conventional pairwise meta-analyses3, 4, 5 could not generate clear hierarchies for the efficacy and side-effects of available treatments, because many antipsychotic drugs have not been compared head to head,6 and because such analyses could not integrate all the evidence from several comparators. As such, any attempt to create such hierarchies was necessarily impressionistic, and guidelines urgently need accurate information to address this question. We aimed to compare the two prototypal first-generation (haloperidol and chlorpromazine) and 13 second-generation antipsychotic drugs when used in patients with schizophrenia. Our intention was to provide evidence-based hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.
Section snippets
Participants and interventions
We did a multiple-treatments meta-analysis to compare 15 antipsychotic drugs for schizophrenia. Multiple-treatments meta-analysis allows the integration of direct and indirect comparisons of antipsychotic drugs (ie, how two or more drugs compare with a common comparator). We followed the same approach as was used in two previous multiple-treatments meta-analyses, of major depressive disorder7 and bipolar mania.8
Our analysis included studies of people with schizophrenia or related disorders
Results
212 studies reported between October, 1955, and September, 2012, with 43 049 participants, were included in the analysis (details of included studies are shown in appendix pp 41–65; PRISMA41 flowcharts are shown in appendix pp 70–76). The mean duration of illness was 12·4 years (SD 6·6) and the mean age of trial participants was 38·4 years (SD 6·9). Nine studies exclusively examined first-episode patients. In terms of study quality, the reports often did not provide details about randomisation
Discussion
Our multiple-treatments meta-analysis provides evidence-based hierarchies for the efficacy and tolerability of antipsychotic drugs, overcoming the major limitation of conventional pairwise meta-analyses.3, 4, 21 Results for our primary outcome challenge the dogma that the efficacy of all antipsychotic drugs is the same. This notion originated from an influential narrative review published in 1969,45 but it has not been scientifically addressed since.
The efficacy hierarchy generated by our
Acknowledgments
We thank Julian Higgins for his work on the protocol; Anna Chaimani for assistance with the statistical analysis; and Claudia Leucht, Maximilian Huhn, Markus Dold, Haoyin Cao, and Magdolna Tardy for their help in preparing the report. For sending us information about their studies, we thank Ebrahim Abdolahian, Christian Barnas, Michael Berk, Warrick Brewer, Roberto Cavallaro, Eva Ceskova, Mark Corrigan, Jair de Jesus Mari, Wolfgang Fleischhacker, Kotaro Hatta, Tzung-Jeng Hwang, Peter Jones,
References (60)
- et al.
Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012) - et al.
Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis
Lancet
(2009) - et al.
Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis
Lancet
(2009) - et al.
Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis
Lancet
(2011) - et al.
Validity of indirect comparisons in meta-analysis
Lancet
(2007) - et al.
Imputing missing standard deviations in meta-analyses can provide accurate results
J Clin Epidemiol
(2006) - et al.
Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial
J Clin Epidemiol
(2011) - et al.
A case study of multiple-treatments meta-analysis demonstrates that covariates should be considered
J Clin Epidemiol
(2009) - et al.
Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment
Schizophr Res
(2005) - et al.
New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis
Lancet
(2003)
Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time
J Clin Epidemiol
Antipsychotic drugs: technologies and global markets
Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis
BMJ
A meta-analysis of the efficacy of second-generation antipsychotics
Arch Gen Psychiatry
A meta-analysis of head to head comparisons of second generation antipsychotics in the treatment of schizophrenia
Am J Psychiatry
Inconsistency between direct and indirect comparisons of competing interventions: meta-epidemiological study
BMJ
International consensus study of antipsychotic dosing
Am J Psychiatry
The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements
Schizophr Bull
World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance
World J Biol Psychiatry
Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care (update)
How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials
Mol Psychiatry
Haloperidol versus placebo for schizophrenia
Cochrane Database of Syst Rev
Chlorpromazine versus placebo for schizophrenia
Cochrane Database Syst Rev
Cochrane Schizophrenia Group Specialised Register
Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis
Ann Intern Med
Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis
CNS Drugs
Cochrane handbook for systematic reviews of interventions, version 5.1.0
Cited by (1975)
Identification of key modules in metabolic syndrome induced by second-generation antipsychotics based on co-expression network analysis
2024, Computational and Structural Biotechnology JournalClozapine metabolism and cardiotoxicity: A prospective longitudinal study
2024, International Journal of CardiologyB-GOS alleviates olanzapine-induced lipid disturbances in mice by enriching Akkermansia and upregulation of PGRMC1-Wnt signaling
2024, Food and Chemical ToxicologyEscitalopram-induced QTc prolongation and its relationship with KCNQ1, KCNE1, and KCNH2 gene polymorphisms
2024, Journal of Affective Disorders